PHD1 regulates p53‐mediated colorectal cancer chemoresistance
Abstract Overcoming resistance to chemotherapy is a major challenge in colorectal cancer (CRC) treatment, especially since the underlying molecular mechanisms remain unclear. We show that silencing of the prolyl hydroxylase domain protein PHD1, but not PHD2 or PHD3, prevents p53 activation upon chem...
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| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Springer Nature
2015-08-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.201505492 |
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| author | Sofie Deschoemaeker Giusy Di Conza Sergio Lilla Rosa Martín‐Pérez Daniela Mennerich Lise Boon Stefanie Hendrikx Oliver DK Maddocks Christian Marx Praveen Radhakrishnan Hans Prenen Martin Schneider Johanna Myllyharju Thomas Kietzmann Karen H Vousden Sara Zanivan Massimiliano Mazzone |
| author_facet | Sofie Deschoemaeker Giusy Di Conza Sergio Lilla Rosa Martín‐Pérez Daniela Mennerich Lise Boon Stefanie Hendrikx Oliver DK Maddocks Christian Marx Praveen Radhakrishnan Hans Prenen Martin Schneider Johanna Myllyharju Thomas Kietzmann Karen H Vousden Sara Zanivan Massimiliano Mazzone |
| author_sort | Sofie Deschoemaeker |
| collection | DOAJ |
| description | Abstract Overcoming resistance to chemotherapy is a major challenge in colorectal cancer (CRC) treatment, especially since the underlying molecular mechanisms remain unclear. We show that silencing of the prolyl hydroxylase domain protein PHD1, but not PHD2 or PHD3, prevents p53 activation upon chemotherapy in different CRC cell lines, thereby inhibiting DNA repair and favoring cell death. Mechanistically, PHD1 activity reinforces p53 binding to p38α kinase in a hydroxylation‐dependent manner. Following p53–p38α interaction and chemotherapeutic damage, p53 can be phosphorylated at serine 15 and thus activated. Active p53 allows nucleotide excision repair by interacting with the DNA helicase XPB, thereby protecting from chemotherapy‐induced apoptosis. In accord with this observation, PHD1 knockdown greatly sensitizes CRC to 5‐FU in mice. We propose that PHD1 is part of the resistance machinery in CRC, supporting rational drug design of PHD1‐specific inhibitors and their use in combination with chemotherapy. |
| format | Article |
| id | doaj-art-a3a9d3f5c75441d39d7785a441a85e40 |
| institution | DOAJ |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2015-08-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-a3a9d3f5c75441d39d7785a441a85e402025-08-20T03:05:55ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842015-08-017101350136510.15252/emmm.201505492PHD1 regulates p53‐mediated colorectal cancer chemoresistanceSofie Deschoemaeker0Giusy Di Conza1Sergio Lilla2Rosa Martín‐Pérez3Daniela Mennerich4Lise Boon5Stefanie Hendrikx6Oliver DK Maddocks7Christian Marx8Praveen Radhakrishnan9Hans Prenen10Martin Schneider11Johanna Myllyharju12Thomas Kietzmann13Karen H Vousden14Sara Zanivan15Massimiliano Mazzone16Lab of Molecular Oncology and Angiogenesis, Department of Oncology, KU LeuvenLab of Molecular Oncology and Angiogenesis, Department of Oncology, KU LeuvenCancer Research UK Beatson InstituteLab of Molecular Oncology and Angiogenesis, Department of Oncology, KU LeuvenFaculty of Biochemistry and Molecular Medicine and Biocenter Oulu, University of OuluLab of Molecular Oncology and Angiogenesis, Department of Oncology, KU LeuvenLab of Molecular Oncology and Angiogenesis, Department of Oncology, KU LeuvenCancer Research UK Beatson InstituteCancer Research UK Beatson InstituteDepartment of General, Visceral and Transplantation Surgery, University of HeidelbergDigestive Oncology Department, University Hospitals LeuvenDepartment of General, Visceral and Transplantation Surgery, University of HeidelbergOulu Center for Cell‐Matrix Research, Biocenter Oulu and Faculty of Biochemistry and Molecular Medicine, University of OuluFaculty of Biochemistry and Molecular Medicine and Biocenter Oulu, University of OuluCancer Research UK Beatson InstituteCancer Research UK Beatson InstituteLab of Molecular Oncology and Angiogenesis, Department of Oncology, KU LeuvenAbstract Overcoming resistance to chemotherapy is a major challenge in colorectal cancer (CRC) treatment, especially since the underlying molecular mechanisms remain unclear. We show that silencing of the prolyl hydroxylase domain protein PHD1, but not PHD2 or PHD3, prevents p53 activation upon chemotherapy in different CRC cell lines, thereby inhibiting DNA repair and favoring cell death. Mechanistically, PHD1 activity reinforces p53 binding to p38α kinase in a hydroxylation‐dependent manner. Following p53–p38α interaction and chemotherapeutic damage, p53 can be phosphorylated at serine 15 and thus activated. Active p53 allows nucleotide excision repair by interacting with the DNA helicase XPB, thereby protecting from chemotherapy‐induced apoptosis. In accord with this observation, PHD1 knockdown greatly sensitizes CRC to 5‐FU in mice. We propose that PHD1 is part of the resistance machinery in CRC, supporting rational drug design of PHD1‐specific inhibitors and their use in combination with chemotherapy.https://doi.org/10.15252/emmm.201505492chemotherapy resistancecolorectal cancerDNA repairprolyl hydroxylase domain proteinstumor suppressor p53 |
| spellingShingle | Sofie Deschoemaeker Giusy Di Conza Sergio Lilla Rosa Martín‐Pérez Daniela Mennerich Lise Boon Stefanie Hendrikx Oliver DK Maddocks Christian Marx Praveen Radhakrishnan Hans Prenen Martin Schneider Johanna Myllyharju Thomas Kietzmann Karen H Vousden Sara Zanivan Massimiliano Mazzone PHD1 regulates p53‐mediated colorectal cancer chemoresistance EMBO Molecular Medicine chemotherapy resistance colorectal cancer DNA repair prolyl hydroxylase domain proteins tumor suppressor p53 |
| title | PHD1 regulates p53‐mediated colorectal cancer chemoresistance |
| title_full | PHD1 regulates p53‐mediated colorectal cancer chemoresistance |
| title_fullStr | PHD1 regulates p53‐mediated colorectal cancer chemoresistance |
| title_full_unstemmed | PHD1 regulates p53‐mediated colorectal cancer chemoresistance |
| title_short | PHD1 regulates p53‐mediated colorectal cancer chemoresistance |
| title_sort | phd1 regulates p53 mediated colorectal cancer chemoresistance |
| topic | chemotherapy resistance colorectal cancer DNA repair prolyl hydroxylase domain proteins tumor suppressor p53 |
| url | https://doi.org/10.15252/emmm.201505492 |
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